Monoamine neurotransmitters (i.e. serotonin, dopamine, and noradrenaline) are released into the synaptic cleft in order to stimulate postsynaptic receptor activity. The removal (or inactivation) of monoamine neurotransmitters occurs mainly by a reuptake mechanism into presynaptic terminals. By inhibiting the re-uptake an enhancement of the physiological activity of monoamine neurotransmitters occur.
Noradrenalin and serotonin re-uptake inhibitors are currently used as pharmaceuticals in anti-depressant therapy (Desipramine, Nortriptyline, and Protriptyline are inhihibitors of noradrenaline-reuptake and Imipramine and Amitriptyline are mixed serotonine-reuptake and noradrenaline-reuptake inhibitors).
The pathophysiology of major affective illness is poorly understood, and several neurotransmitters have been implicated in the pathophysiology of major depression. However, several lines of preclinical and clinical evidence indicate that an enhancement of serotonin-mediated neurotransmission might underlie the therapeutic effect of the most recent and currently used drugs in anti-depressant therapy, such as fluoxetine, citalopram and Paroxetine.
Paradoxical serotonin re-uptake inhibitors inhibit the serotonin transporter within minutes whereas their full anti-depressant effect is seen only after three to four weeks of treatment, indicating that re-uptake inhibition per se is not responsible for the antidepressant response, but rather that further adaptive changes underlie and/or contribute to their therapeutic effect. The delayed onset of anti-depressant effect is considered to be a serious drawback to currently used monoamine re-uptake inhibitors.
The compounds provided herewith are potent serotonin (5-hydroxy-tryptamine, 5-HT) re-uptake inhibititors. The compounds of the invention also have noradrenaline and dopamine re-uptake inhibiting activity but the serotonin re-uptake inhibiting activity of the compounds of the invention is stronger than the dopamine re-uptake inhibiting activity of the compounds.
Further, a strong dopamine re-uptake inhibiting activity is currently considered with the risk of undesirable central stimulating effects. On the other hand, an activating effect on the mesolimbic dopamine system is currently believed to underlay the commen mechanism of current antidepressant treatment by a mechanism which enhances the endogenous reward system. Compounds with a strong serotonin re-uptake inhibiting activity combined with a well balanced dopamine re-uptake inhibiting activity may therefore provide agents with a rapid onset of anti-depressant effect.
The serotonergic neural system of the brain have been shown to influence a variety of physiologic functions, and the compounds of the present invention are believed to have the ability to treat in mammals, including humans, a variety of disorders associated with these neural systems such as eating disorders, depression, obcessive compulsive disorders, panic disorders, alcoholism, pain, memory deficits and anxiety. Therefore, the present invention also provides methods of treating several disorders linked to decreased neurotransmission of serotonin in mammals. Included among these disorders are depression and related disorders such as pseudodementia or Ganser's syndrome, migraine pain, bulimia, obesity, pre-menstrual syndrome or late luteal phase syndrome, alcoholism, tobacco abuse, panic disorder, anxiety, post-traumatic syndrome, memory loss, dementia of ageing, social phobia, attention deficit hyperactivity disorder, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, mutism or trichotillomania.